Water-soluble phytocannabinoid formulations

ABSTRACT

Methods and formulations for increasing the water solubility and/or bioavailability of a phytocannabinoid compound is disclosed herein. In one example, a topical formulation includes a water-soluble phytocannabinoid emulsion including a phytocannabinoid oil which includes a phytocannabinoid compound, and a non-ionic surfactant. The weight ratio of phytocannabinoid compound content to non-ionic surfactant can be from 1:10,000 to 1:5.

The present application is a continuation of U.S. patent applicationSer. No. 16/103,270, filed Aug. 14, 2018, which is a continuation ofU.S. patent application Ser. No. 15/911,990, filed on Mar. 5, 2018, nowU.S. Pat. No. 10,046,018 issued on Aug. 14, 2018, which is acontinuation of U.S. patent application Ser. No. 14/791,181, filed onJul. 2, 2015, now U.S. Pat. No. 9,907,823 issued on Mar. 6, 2018, whichclaims the benefit of U.S. Provisional Patent Application No.62/077,153, filed on Nov. 7, 2014, each of which is incorporated hereinby reference.

BACKGROUND

Hemp is an industrial plant that can be grown on a large scale in manyregions of the world. Hemp, also known as cannabis, has a long historyof use in humans as an anticonvulsant, sedative, hypnotic,anti-depressant, analgesic, anti-inflammatory, anti-emetic,anti-spasmodic, and appetite-stimulator. Cannabis contains a broadspectrum of chemical compounds including: phytocannabinoids, terpenoids(essential oils), flavonoids, enzymes, and steroids. Whiledelta-9-tetrahydrocannabinol (delta-9-THC) is believed to be theprinciple psychoactive component of hemp, other phytocannabinoids (suchas cannabidiol, cannabinol, and cannabichromene) are thought to possessnumerous medicinal properties without the psychoactive effects ofdelta-9-THC. However, the oral bioavailability of thesephytocannabinoids is limited. For example, the oral bioavailability ofcannabidiol was found to be about 6%. The limited bioavailability ofthese phytocannabinoids is believed to be because cannabidiol is anatural fat soluble compound that is hydrophobic and thus insoluble inwater. Due to the many desirable properties of phytocannabinoids, suchas cannabidiol, it would be advantageous to provide improved, stable,water soluble formulations, with enhanced bioavailability for humanconsumption in various convenient formulations such as juices, softdrinks, bottled water, and liquid concentrates.

BRIEF DESCRIPTION OF THE DRAWINGS

Features and advantages of the technology disclosed herein will beapparent from the detailed description that follows, taken inconjunction with the accompanying figures that together illustratefeatures of the technology. It is understood that these figures merelydepict exemplary embodiments and are not, therefore, to be consideredlimiting in scope. Furthermore, it will be readily appreciated that thecomponents, as generally described and illustrated in the figuresherein, could be arranged and designed in a wide variety of differentconfigurations.

FIG. 1 shows the blood plasma levels of three rats administered a sampleformulation of the water soluble cannabidiol oil as disclosed hereinover a 24 hour period; and

FIG. 2 shows a comparison of the total absorption for a sampleformulation of the water soluble cannabidiol oil as disclosed herein tothe absorption of a commercially available cannabidiol oil.

These figures are provided to illustrate various aspects of thetechnology and are not intended to be limiting in terms of results orcomponents unless otherwise limited by the claims.

DETAILED DESCRIPTION

Reference will now be made to the exemplary embodiments and specificlanguage will be used herein to describe the same. It will neverthelessbe understood that no limitation of the scope of the invention isthereby intended. Alterations and further modifications of the inventivefeatures illustrated herein, and additional applications of theprinciples of the disclosure as illustrated herein, which would occur toone skilled in the relevant art and having possession of thisdisclosure, are to be considered within the scope of the disclosure. Itis also to be understood that this disclosure is not limited to theparticular configurations, process steps and materials disclosed herein,as these may vary to some degree. Further, it is to be understood thatthe terminology used herein is used for the purpose of describingparticular embodiments only, and is not intended to be limiting as thescope of the present disclosure.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a non-ionic surfactant” includes reference to one or more of suchnon-ionic surfactants.

The formulations described herein can be used in the context of“combination therapy” or “adjunct therapy” with other drugs to treat orotherwise provide a benefit with respect to a disease or other malady.This combination therapy can be sequential therapy where the patient istreated first with one drug and then the other or the two drugs aregiven simultaneously. The present disclosure includes combinationtherapy or adjunct therapy using the water soluble formulations of thepresent disclosure.

As used herein, the term “clear” is intended to relate to a solution oraqueous solution containing the natural lipophilic compound in a watercontaining solution (e.g. a beverage) that is free of visible particlesof undissolved compound. A clear solution or clear aqueous solutionincludes both solutions as well as very fine dispersions that remainclear upon sitting undisturbed for one hour or more. Essentially novisible (to the naked eye) particles or micelles are present. When theclear aqueous solution is a beverage, the clear aqueous solution maysometimes not need to be shaken prior to consuming.

A “non-alcoholic” formulation, as used herein, is a formulation thatdoes not include or includes only de minimis or trace amounts ofmethanol, ethanol, propanol or butanol.

The term “non-aprotic solvated,” as used herein, means that watersoluble aprotic solvents are absent or are included only in de minimisor trace amounts.

“Nutraceutical” includes lipophilic compounds or essential oils derivedfrom natural sources such as cannabis, blueberries, grapes, otherberries, soybeans, cocoa beans, tomatoes, green tea, turmeric, citrusfruit, other botanical sources, compounds produced synthetically as highpurity compounds of an identical chemical structure to a naturallyderived source, or produced through fermentation.

Exemplary lipophilic natural compounds commonly used in nutraceuticalsinclude the phytocannabinoids such as cannabidiol, terpenoids, essentialoils such as β-caryophyllene, caryophyllene, pinene, linalool, limonene,phytol, nerolidol, myrcene, fatty acids such as linoleic, lenolenic,palmitic, stearidonic, stearic, oleic acid, arachidonoylethanolamide(anandamide), compounds such as co-enzyme Q-10, pterostilbene, lutein,lycopene, other essential flavor oils such as citrus oil, grapefruitseed extract, green tea extract, EGCG, cocoa extract, epigallocatechingallate, epigallocatechin, epicatechin, catechin, epicatechin gallate,quercetin, curcumin, turmeric, D-limonene, lemon oil, carotenoids,astaxanthin, or phosphatidylserine.

The term “pharmaceutically acceptable salts” or “salts” is meant toinclude salts of the active compounds described herein which areprepared with nontoxic or relatively nontoxic acids or bases, dependingon the particular substituent moieties found on the compounds describedherein. When formulations of the present disclosure contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Whenformulations of the present disclosure contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredbase, either neat or in a suitable inert solvent. Certain specificformulations of the present disclosure contain both basic and acidicfunctionalities that allow the compounds to be converted with eitherbase or acid addition salts. Examples of pharmaceutically acceptablebase addition salts include sodium, potassium, calcium, ammonium,organic amino, magnesium salt, or similar salts thereof. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like. The neutral forms of thecompounds are typically regenerated by contacting the salt with a baseor acid and isolating the parent compound in the conventional manner.The parent form of the compound can differ from the various salt formsin certain physical properties, such as, solubility in polar solvents.

As used herein, “phytocannabinoid” or “phytocannabinoid compound” meansany of the following non-psychoactive compounds derived from Cannabis,and typically from the hemp plant. Exemplary phytocannabinoids includecannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC),cannabichromenic acid (CBCA), cannabidiolic acid (CBDA), cannabidivarin(CBDV), cannabigerol (CBG), cannabigerolic acid (CBGA), orcannabigerivarin (CBGV). Cannabidiol (CBD) is one of the most abundantphytocannabinoids found in hemp.

“Phytocannabinoid oil” refers to oils that include phytocannabinoidcompounds as well as other components that may also be present in theoil, such as small amounts of fatty acids such as oleic acid, palmiticacid, stearic acid, and octadecadienoic acid, etc., as well as essentialoils. Depending on the extract, the phytocannabinoid content can bepresent at from less than 1 wt % (e.g., hemp oil) to up to 99 wt % orgreater (highly purified extracts). In some examples, thephytocannabinoid oil can have from 20 wt % phytocannabinoid to 98 wt %phytocannabinoid compound(s). To illustrate, an 80 wt % extract oil caninclude 80 wt % CBD, for example.

As used herein, “prodrugs” are those compounds that readily undergochemical changes under physiological conditions to provide theformulations of the present disclosure. Prodrugs can also be by chemicalor biochemical methods in an ex vivo environment. For example, prodrugscan be slowly converted to the formulations of the present disclosurewhen placed in a transdermal patch reservoir with a suitable enzyme orchemical reagent.

As used herein, “subject” or “patient” is an organism that is treatedusing one of the methods of the present disclosure. In some embodiment,the subject is a mammalian subject, such as a human or a domesticanimal.

A “water-solubilized” formulation, as used herein, includes the naturallipophilic compound, esters, metabolites, prodrugs, or salt thereof, anon-ionic surfactant, other compositional components, and water (e.g. awater containing liquid), but often does not include organic solvents(e.g. ethanol). In some embodiments, the water solubilized formulationis a transparent water soluble formulation.

As used herein, a plurality of items, compositional elements, and/ormaterials may be presented in a common list for convenience. However,these lists should be construed as though each member of the list isindividually identified as a separate and unique member. Thus, noindividual member of such list should be construed as a de factoequivalent of any other member of the same list solely based on theirpresentation in a common group without indications to the contrary.Removal of single components from a list or combining multiple liststogether are considered to be fully supported herein as if eachcomponent were listed separately.

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited. Asan illustration, a numerical range of “about 0.01 to 2.0” should beinterpreted to include not only the explicitly recited values of about0.01 to about 2.0, but also include individual values and sub-rangeswithin the indicated range. Thus, included in this numerical range areindividual values such as 0.5, 0.7, and 1.5, and sub-ranges such as from0.5 to 1.7, 0.7 to 1.5, and from 1.0 to 1.5, etc. This same principleapplies to ranges reciting only one numerical value. Furthermore, suchan interpretation should apply regardless of the breadth of the range orthe characteristics being described.

With this in mind, many natural compounds (nutraceuticals) have beenfound to be potential therapeutic agents. Exemplary nutraceuticalsinclude: the flavonoids or flavanols from green tea and cocoa (or darkchocolate) such as epigallocatechin gallate, epigallocatechin,epicatechin, catechin, and epicatechin gallate; flavonoids fromgrape-type fruits or berries such as resveratrol (3, 5,4′-trihydroxystilbene); and pterostilbene derived from natural sourcessuch as blueberries, grapes, other berries, or other botanical sources.Other natural compounds found to be beneficial for health include lutein(extracted from marigold flowers), lycopene (extracted from tomatoes),curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione,99% by HPLC), turmeric, co-enzyme Q-10 (ubidecarenone, ubiquinone,ubiquinol), epigallocatechin gallate (EGCG) (derived from green tea),(−)-epicatechin (derived from cocoa powder), essential oils (such ascitrus essential oils, grapefruit seed extracts, and D-limonene),carotenoids, astaxanthin, and phosphatidylserine.

Many flavonoids are lipophilic or fat soluble and exhibit very lowsolubility in water (hydrophobic). Some flavonoids can be virtuallyinsoluble in water, and animal pharmacokinetic studies of oral doseshave demonstrated very low bioavailability. Human studies with green teaextracts standardized to the active catechins, have demonstrated verylow absorption, usually less than 1 wt % of the oral dose in animal orhuman studies. In order for nutraceuticals or any therapeutic molecularsubstance to be absorbed through the gastrointestinal tract, enter theblood, and eventually reach the organs and cells inside the body, themolecules should be finely dispersible or dissolvable in the aqueousphase of the intestinal fluid. Without dissolution, the substance willtypically pass through the GI-tract and will not be absorbed atdesirable concentrations.

As mentioned, one type of nutraceutical includes the phytocannabinoidsderived from hemp such as cannabidiol. Phytocannabinoids are lipophiliccompounds that are capable of being used therapeutically. Despite this,these compounds tend to be insoluble in water, often float on top ofwater, and will not form a stable water soluble solution that is crystalclear and remains that way over time. Hemp also contains various otheressential oils or terpenes, and fatty acids that are lipophilic andinsoluble in water. Some mixtures of certain fatty acids such as oleicacid have beneficial effects on other fatty acids contained in the dietby stimulating oxidation of those fatty acids. Exemplary potentialnutraceutical components that can be derived from hemp are included inTables A and B below.

TABLE A Hemp Oil Fatty Acids Molecular CAS Common Name Scientific NameWeight Number Palmitic acid Hexadecanoic acid 256.42 57-10-3 Stearicacid Octadecanoic acid 284.48 57-11-4 Oleic acid 9c-octadecenoic acid282.46 112-80-1 Linoleic acid 9c,12c-octadecadienoic 280.45 60-33-3 acidγ-linoleic acid 6c,9c,12c- 278.43 506-26-3 (GLA) octadecatrienoic acidα-linolenic acid 9c,12c,15c- 278.433 463-40-1 (ALA) octadecarienoic acidStearidonic acid 6c,9c,12c,15c- 276.417 20290-75-9 octadecatetraenoicacid

TABLE B Hemp Oil Fatty Acid Profile (major fatty acids) Common NameScientific Name Wt % Palmitic acid (C16:0) Hexadecanoic acid 5-9 Stearicacid (C18:0) Octadecanoic acid 2-3 Oleic acid (C18:1) 9c-octadecencoicacid  8-16 Linoleic acid (C18-2) 9c,12c-octadecadienoic acid 50-70γ-linolenic acid (GLA) (18:3) 6c,9c,12c- 1-6 octadecatrienoic acidα-linolenic acid (ALA) (C18:3) 9c,12c,15c- 15-30 octadecarienoic acidArachidic acid (C20:0) Icosanoic acid 0-2 Stearidonic acid (SDA)6c,9c,12c,15c- 0.5-1.5 octadecatetraenoic acid Palmitoleic acid (C16:1)9Z-hexadec-9-enoic acid   0-0.5The principle fatty acids (present in amounts greater than 1 wt %) foundin hemp are linoleic, linolenic, oleic, palmitic, and stearic acids.

With this in mind, the present disclosure provides water-solublephytocannabinoid formulations including a phytocannabinoid or acombination thereof and a non-ionic surfactant. For example, awater-soluble phytocannabinoid emulsion formulation can include aphytocannabinoid oil and a non-ionic surfactant, wherein the weightratio of phytocannabinoid content to non-ionic surfactant is from1:10,000 to 1:5. In another example, the formulation can be dissolved orfinely dispersed in water.

In another example, a water-soluble phytocannabinoid emulsionformulation can include a phytocannabinoid oil containing aphytocannabinoid selected from the group consisting of cannabidiol(CBD), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid(CBCA), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol(CBG), cannabigerolic acid (CBGA), cannabigerivarin (CBGV), estersthereof, metabolites thereof, and mixtures thereof; and a non-ionicsurfactant. The phytocannabinoid content and the non-ionic surfactantcan be present in the formulation at a weight ratio from about 1:1,000to about 1:5.

These formulations can also include mixtures of fatty acids and/oressential oils found in hemp. In some embodiments, the fatty acids canbe present in amounts that are not naturally present in hemp oil. Inother embodiments, the formulation can further comprise essential oils(terpenes), other fatty acids, esters thereof, salts thereof,metabolites thereof, prodrugs thereof, and mixtures thereof.

The phytocannabinoid compound can be selected from cannabidiol (CBD),cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA),cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG),cannabigerolic acid (CBGA), and/or cannabigerivarin (CBGV). In oneembodiment, the phytocannabinoid compound is cannabidiol. In anotherembodiment, the formulation can include a phytocannabinoid compound andcertain amounts of fatty acids such as oleic acid, palmitic acid,stearic acid, and octadecadienoic acid, as well as essential oils. Insome other embodiments, the water-soluble formulations containingphytocannabinoid compounds and/or fatty acids can be formulated for usein beverages or liquid concentrates.

The non-ionic surfactant can be a surface active agent that tends to benon-ionized in neutral solutions. Useful non-ionic surfactants cancomprise non-ionic water soluble mono-, di-, and tri-glycerides;non-ionic water soluble mono- and di-fatty acid esters of polyethyeleneglycol; non-ionic water soluble sorbitan fatty acid esters (e.g.sorbitan monooleates such as SPAN 80 and TWEEN 20 (polyoxyethylene 20sorbitan monooleate)); polyglycolyzed glycerides; non-ionic watersoluble triblock copolymers (e.g.poly(ethyleneoxide)/poly-(propyleneoxide)/poly(ethyleneoxide) triblockcopolymers such as POLOXAMER 406 (PLURONIC F-127), and derivativesthereof. Examples of non-ionic water soluble mono-, di-, andtri-glycerides can include propylene glycol dicarpylate/dicaprate (e.g.MIGLYOL 840), medium chain mono- and diglycerides (e.g. CAPMUL andIMWITOR 72), medium-chain triglycerides (e.g. caprylic and caprictriglycerides such as LAVRAFAC, MIGLYOL 810 or 812, CRODAMOL GTCC-PN,and SOFTISON 378), long chain monoglycerides (e.g. glyceryl monooleatessuch as PECEOL, and glyceryl monolinoleates such as MAISINE), polyoxylcastor oil (e.g. macrogolglycerol ricinoleate, macrogol glycerolhydroxystearate, macrogol cetostearyl ether), and derivatives thereof.Non-ionic water soluble mono- and di-fatty acid esters of polyethyeleneglycol can include d-α-tocopheryl polyethyleneglycol 1,000 succinate(TPGS), poyethyleneglycol 660 12-hydroxystearate (SOLUTOL HS 15),polyoxyl oleate and stearate (e.g. PEG 400 monostearate and PEG 1750monostearate), and derivatives thereof. Polyglycolyzed glycerides caninclude polyoxyethylated oleic glycerides, polyoxyethylated linoleicglycerides, polyoxyethylated caprylic/capric glycerides, and derivativesthereof. Specific examples include LABRAFIL M-1944CS, LABRAFIL M-2125CS,LABRASOL, SOFTIGEN, and GELUCIRE. In some embodiments, the non-ionicsurfactant is a polyoxyl castor oil, or a derivative thereof.

In some embodiments, the water soluble formulations can comprise thephytocannabinoid compound, metabolite, ester, prodrug, or salt thereof,and various fatty acids in an emulsion. The phytocannabinoid emulsioncan be combined with water to form a transparent water solubleformulation. A “transparent water soluble formulation,” as disclosedherein, refers to a formulation that can be seen through with the nakedeye and is optionally colored. In some embodiments, the transparentwater soluble formulation does not contain particles (e.g. particles ofundissolved lipophilic compound) visible to the naked eye. In someembodiments, the water soluble formulation does not include visiblemacro-micelles (micelles visible to the naked eye) in water. In certainembodiments, light may be transmitted through the transparent watersoluble formulations without diffusion or scattering. Thus, in someembodiments the transparent water soluble formulations are not opaque,cloudy, or milky-white. Transparent water soluble formulations asdisclosed herein do not include milky-white emulsions or suspensions invegetable oil such as corn oil. Transparent water soluble formulationsare also typically not formed by first dissolving the compound inalcohol, and then mixed with water. Thus, in some embodiments, the watersoluble formulation can comprise a non-alcoholic formulation.

In yet another embodiment, the formulation can comprise a non-aproticsolvated formulation. Water soluble aprotic solvents are water solublenon-surfactant solvents in which the hydrogen atoms are not bonded to anoxygen or nitrogen and therefore cannot donate a hydrogen bond.

In still other embodiments, the water soluble formulation does notinclude (or includes only de minimis or trace amounts) a non-polaraprotic solvent. Non-polar aprotic solvents are aprotic solvents whosemolecules exhibit a molecular dipole of zero or approximately zero.Exemplary non-polar aprotic solvents can include hydrocarbons, such asalkanes, alkenes, and alkynes.

In further embodiments, the water soluble formulation does not include(or includes only de minimis or trace amounts) a polar aprotic solvent.Polar aprotic solvents are aprotic solvents whose molecules exhibit amolecular dipole moment but whose hydrogen atoms are not bonded to anoxygen or nitrogen atom. Examples of polar aprotic solvents includealdehydes, ketones, dimethyl sulfoxide (DMSO), and dimethyl formamide(DMF). In other embodiments, the water soluble formulation does notinclude (or includes only de minimis or trace amounts) of dimethylsulfoxide. Thus, in some embodiments, the water soluble formulation doesnot include DMSO. In another embodiment, the water soluble formulationdoes not include DMSO or ethanol.

The water soluble formulation of the present disclosure can compriseformulations dissolved in water (i.e. aqueous formulations), as well asformulations without water, that are suitable for use in soft-gelatincapsules, that form soluble solutions in gastric fluid after ingestion.In most embodiments, the water soluble formulations form a transparentwater soluble formulation when added to water.

In some embodiments, the water soluble formulation consists essentiallyof the phytocannabinoid compound (e.g., the lipophilic natural compoundper se or the ester, metabolite, prodrug, and/or salt thereof), and anon-ionic surfactant. In one embodiment, the phytocannabinoid compoundis cannabidiol. Where a water soluble formulation “consists essentiallyof” the lipophilic natural compound and a non-ionic surfactant, theformulation includes the lipophilic natural compound and the non-ionicsurfactant, and optionally additional components widely known in the artto be useful in nutraceutical formulations, such as preservatives,excipients, pH modifiers, taste enhancers, buffers, water, etc. As aspecific example, a water soluble formulation that “consists essentiallyof” the phytocannabinoid compound, ester, or salt thereof does notinclude any significant formulation additive or component that wouldmaterially affect the basic and novel properties of the invention.

In other embodiments, a free form of the compound can prepared due to ahigher concentration of the active compound. Certain formulations of thepresent disclosure can exist in unsolvated forms as well as solvatedforms, including hydrated forms. In general, the solvated forms areequivalent to unsolvated forms and are encompassed within the scope ofthe present disclosure. Certain formulations of the present disclosuremay exist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated by the presentdisclosure and are intended to be within the scope of the presentinvention.

Certain formulations of the present disclosure possess asymmetric carbonatoms (optical centers) or double bonds, and the racemates,diastereomers, tautomers, geometric isomers and individual isomers areencompassed within the scope of the present disclosure.

The formulations of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe formulations of the present disclosure, whether radioactive or not,are encompassed within the scope of the present disclosure.

In addition to salt forms, the present disclosure provides compounds,which are in a prodrug form, metabolites, esters, or the like.

In some embodiments, the phytocannabinoid compound is present in thewater soluble emulsion formulation at a concentration of at least 0.1 wt%, 1%, 5%, 10%, 20%, 25%, 30%, 35%, 45%, 45%, or 50% by weight. In otherembodiments, the compounds can be present in the water soluble emulsionformulation at a concentration from 0.01% to 80%, 0.1% to 80%, 1% to80%, 5% to 50%, 10% to 35%, or 20% to 25% (by weight). In someembodiments, the phytocannabinoid compound is present in the watersolubilized formulation (where water is added to the emulsion) at aconcentration of at least 0.01 wt %, 0.1 wt %, 1%, 5%, 10%, 20%, 25%,30%, 35%, 45%, 45%, or 50% by weight. In other embodiments, thecompounds can be present in the water solubilized formulation (where thewater is added) at a concentration from 0.001% to 50%, 0.01% to 50%,0.1% to 50%, 1% to 40%, 5% to 35%, or 10% to 25% (by weight).

The compound may also be present (e.g. in a beverage formulation) at aconcentration with added water from 0.5 mg to 250 mg per 3.3 fluid oz,or around 2 mg/ml to 10 mg/ml. In other embodiments, the compound ispresent at a concentration from 0.01 mg/ml to 50 mg/ml. Theconcentration range would be from 0.1% to 30% by weight for thesurfactant, or 0.01 mg/ml to 50 mg/ml for the phytocannabinoid compound,with a more typical concentration around 10 mg/ml of actualphytocannabinoid, depending on the purity of the phytocannabinoid oil.This can be, for examples, at a ratio of the phytocannabinoid oil tosurfactant of 1:1,000 to 1:5 by weight (about 0.1 wt % to about 20 wt %phytocannabinoid oil in the oil/surfactant emulsion). That being said,as the phytocannabanoid content in oil extracts can range from less than1 wt % phytocannabinoid compound to essentially 100 wt %phytocannabanoid, the phytocannabanoid content to non-ionic surfactantweight ratio can be from 1:10,000 to 1:5, from 1:5,000 to 1:5, or from1:1000 to 1:5. In another example, the phytocannabinoid compound may bepresent at about 0.1 mg/ml to 50 mg/ml, or around 20 mg/ml, or at least1 mg/ml (in cases where water is present, or when water is not present).When water is not present, the phytocannabinoid compound may be presentat from 0.1 mg/ml to 75 mg/ml in some examples.

In another aspect, the present disclosure provides a method forenhancing the bioavailability of the phytocannabinoid compounds in asubject. The method includes combining a phytocannabinoid oil (includingmetabolites or salt thereof) with a non-ionic surfactant to form asurfactant-lipophilic compound mixture. The surfactant-lipophiliccompound mixture may be administered to the subject directly, or admixedwith water and administered, thereby enhancing the bioavailability ofthe phytocannabinoid compound. The bioavailability is enhanced comparedto the bioavailability of the compound in the absence of non-ionicsurfactant.

In another aspect, the present disclosure provides a method ofdissolving a phytocannabinoid (including a metabolite or salt thereof)in water. The method includes combining a phytocannabinoid oil with aphytocannabinoid therein with a non-ionic surfactant that has beenwarmed to form a surfactant-phytocannabinoid mixture. Subject non-ionicsurfactants may be assayed for their ability to solubilize thephytocannabinoid oil using any appropriate method. Typically, a heated,non-ionic surfactant can be contacted with the phytocannabinoid oil andmixed mechanically and/or automatically using a shaker or heated mixingvessel device. This can be done without other added ingredients, but insome examples, warm water may be optionally added. In one example, thewater may be used where the compound and/or surfactant is in powderform. In one embodiment, the non-ionic surfactant can be warmed to atemperature of at least 90° F. In another embodiment, the non-ionicsurfactant can be warmed to a temperature of at least 200° F. In theseexamples, the solution is heated to a temperature of at least 90° F., atleast 120° F., at least 150° F., or at least 200° F. The heatingtemperature can be selected to avoid chemical breakdown of thelipophilic natural compound or lipophilic natural compound metaboliteand non-ionic surfactant. This temperature is usually, but not limited,to within the range from about 90° F. to about 180° F. In one embodimentthe temperature range is from about 100° F. to about 125° F.

In one embodiment, when the formulation is for inclusion in asoft-gelatin capsule, the warm phytocannabinoid compound and surfactantcan be combined with other oils, such as oleic acid or olive oil, orwithout these oils, and filled into capsules without water. The heatingtemperature can be selected to avoid chemical breakdown of thephytocannabinoid compound and/or non-ionic surfactant. The temperaturerange is usually, but not limited, to a range from about 90° F. to about180° F. In one embodiment the temperature range is from about 100° F. toabout 125° F.

The surfactant-phytocannabinoid mixture can then be combined with waterthat has been warmed, thereby dissolving (or very finely dispersing) thecompound in water. In one embodiment, the water can be warmed to atemperature of at least 90° F. In another embodiment, the water can bewarmed to a temperature of at least 200° F. The temperature is usually,but not limited, to within the range from about 90° F. to about 180° F.In one embodiment, the temperature range is from about 100° F. to about125° F. In some embodiments, the resulting solution is a water solubleformulation or transparent water soluble formulation as described above.For example, the resulting solution may be a water soluble formulationthat can be a crystal clear solution, with no particles visible to thenaked eye.

The resulting solution may be visually inspected for colloidal particlesto determine the degree of solubility of the compound. Alternatively,the solution may be filtered and analyzed to determine the degree ofsolubility. For example, a spectrophotometer may be used to determinethe concentration of the compound present in the filtered solution.Typically, the test solution is compared to a positive controlcontaining a series of known quantities of pre-filtered lipophilicnatural compound solutions to obtain a standard concentration versusUV/VIS absorbance curve. Alternatively, high performance liquidchromatography may be used to determine the amount of the compound insolution.

High throughput solubility assay methods are known in the art.Typically, these methods involve automated dispensing and mixing ofsolutions with varying amounts of non-ionic surfactants, lipophilicnatural compound, and optionally other co-solvents. The resultingsolutions may then be analyzed to determine the degree of solubilityusing any appropriate method. For example, the Millipore MultiScreenSolubility filter Plate® with modified track-etched polycarbonate, 0.4μm membrane is a single-use, 96-well product assembly that includes afilter plate and a cover. This device is intended for processing aqueoussolubility samples in the 100-300 μL volume range. The vacuum filtrationdesign is compatible with standard, microtiter plate vacuum manifolds.The plate is also designed to fit with a standard, 96-well microtiterreceiver plate for use in filtrate collection. The MultiScreenSolubility filter Plate® has been developed and QC tested for consistentfiltration flow-time (using standard vacuum), low aqueous extractablecompounds, high sample filtrate recovery, and its ability to incubatesamples as required to perform solubility assays. The low-bindingmembrane has been specifically developed for high recovery of dissolvedorganic compounds in aqueous media.

The aqueous solubility assay allows for the determination ofphytocannabinoid solubility by mixing, incubating, and filtering asolution in the MultiScreen Solubility filter plate. After the filtrateis transferred into a 96-well collection plate using vacuum filtration,it is analyzed by UV/VIS spectroscopy to determine solubility.Additionally, LC/MS or HPLC can be used to determine compoundsolubility, especially for compounds with low UV/VIS absorbance and/orcompounds with lower purity. For quantification of aqueous solubility, astandard calibration curve may be determined and analyzed for eachcompound prior to determining aqueous solubility.

Test solutions may be prepared by adding an aliquot of concentrated drugor compound. The solutions are mixed in a covered 96-well MultiScreenSolubility filter plate for 1.5 hours at room temperature. The solutionsare then vacuum filtered into a 96-well, polypropylene, V-bottomedcollection plate to remove any insoluble precipitates. Upon completefiltration, 160 μL per well are transferred from the collection plate toa 96-well UV analysis plate and diluted with 40 μL per well ofacetonitrile. The UV/VIS analysis plate is scanned from 260 nm to 500 nmwith a UV/VIS microplate spectrometer to determine the absorbanceprofile of the test compound.

Thus, one skilled in the art may assay a wide variety of non-ionicsurfactants to determine their ability to solubilize lipophilic naturalcompounds.

Also presented herein are pharmaceutical compositions. Thepharmaceutical composition may include the phytocannabinoid, such ascannabidiol, an ester or metabolite of a phytocannabinoid, a non-ionicsurfactant, and a pharmaceutically acceptable excipient.

The pharmaceutical composition can be in any appropriate dosage form canbe used for administration of the water soluble formulation of thepresent disclosure, such as oral, parenteral, and topical dosage forms.Oral preparations include tablets, pills, powder, dragees, capsules(e.g. soft-gel capsules), liquids, lozenges, gels, syrups, slurries,beverages, suspensions, etc., suitable for ingestion by the patient. Theformulations of the present disclosure can also be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. The formulationscan also be administered by inhalation, for example, intranasally. Inother embodiments, the formulations of the present disclosure can beadministered transdermally by a topical route, formulated as applicatorsticks, solutions, suspensions, emulsions, gels, creams, ointments,pastes, jellies, paints, powders, and aerosols. A water solubleformulation as described herein may be sprayed directly onto the skin.In yet another embodiment, the formulations can be administered by inintraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations. Infurther embodiments the formulations can be adapted for oraladministration. The formulations can also be delivered as microspheresfor slow release in the body. For example, microspheres can beadministered via intradermal injection of drug-containing microspheres,which slowly release subcutaneously, or, as microspheres for oraladministration. Both transdermal and intradermal routes can affordconstant delivery for weeks or months.

Pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances, which may also act as diluents, flavoringagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. Details on techniques for formulation andadministration of solid form pharmaceuticals are well described in thescientific and patent literature.

Suitable carriers can include magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch (from corn, wheat, rice,potato, or other plants), gelatin, tragacanth, a low melting wax, cocoabutter, sucrose, mannitol, sorbitol, cellulose (such as methylcellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose), and gums (including arabic and tragacanth), aswell as proteins such as gelatin and collagen. If desired,disintegrating or co-solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate. In powders, the carrier can be afinely divided solid, which is in a mixture with the finely dividedactive component. In tablets, the active component can be mixed with thecarrier having the necessary binding properties in suitable proportionsand compacted in the shape and size desired.

Dragee cores can be provided with suitable coatings such as concentratedsugar solutions, which can also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titaniumdioxide, lacquer solutions, suitable organic solvents or solventmixtures, and combinations thereof. Dyes or pigments may be added to thetablets or dragee coatings for product identification or to characterizethe quantity of active compound (i.e., dosage). Pharmaceuticalpreparations of the present disclosure can also be used orally using,for example, push-fit capsules made of gelatin, as well as soft, sealedcapsules made of gelatin and a coating such as glycerol or sorbitol.Push-fit capsules can contain the lipophilic natural compound mixed witha filler or binders such as lactose or starches, lubricants such as talcor magnesium stearate, and optionally stabilizers. In soft capsules, thecompound may be dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycol with orwithout stabilizers.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby allowed to solidify.

Liquid form preparations include solutions, suspensions, beverages, andemulsions, for example, water or water/propylene glycol solutions. Forparenteral injection, liquid preparations can be formulated in solutionin an aqueous polyethylene glycol solution.

Aqueous solutions and beverages suitable for oral use can be prepared bydissolving the active component in water and optionally adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions suitable for oral use can be made by dispersing the finelydivided active component in water with viscous material, such as naturalor synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partialester derived from a fatty acid and a hexitol (e.g., polyoxyethylenesorbitol mono-oleate), or a condensation product of ethylene oxide witha partial ester derived from fatty acid and a hexitol anhydride (e.g.,polyoxyethylene sorbitan mono-oleate). The aqueous suspension can alsocontain one or more preservatives such as ethyl or n-propylp-hydroxybenzoate, one or more coloring agents, one or more flavoringagents, and/or one or more sweetening agents, such as sucrose, aspartameor saccharin. Formulations can be adjusted for osmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations can contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Emulsions can be formulated by combining the phytocannabinoid compoundwith a specific mixture of fatty acids, such as oleic, stearic,palmitic, trans-octadecadienoic acid, and arachidic acids. The emulsionscan contain other essential oils contained in the hemp plant such as theterpenes myrcene, limonene, alpha & beta-pinene, linalool,b-caryophyllene, caryophyllene oxide, humulene, nerolidol, and phytol.The emulsions can contain a thickening agent, such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents can be added to provide apalatable oral preparation, such as glycerol, sorbitol, or sucrose.These formulations can be preserved by the addition of an antioxidantsuch as ascorbic acid. The formulations can also be in the form ofoil-in-water emulsions. The oily phase can be a vegetable oil or amineral oil, described above, or a mixture of these. Suitableemulsifying agents include: naturally-occurring gums, such as gum acaciaand gum tragacanth; naturally occurring phosphatides, such as soybeanlecithin; esters or partial esters derived from fatty acids; and hexitolanhydrides, such as sorbitan mono-oleate; and condensation products ofthese partial esters with ethylene oxide, such as polyoxyethylenesorbitan mono-oleate. The emulsion can also contain sweetening agentsand flavoring agents, as in the formulation of syrups and elixirs. Suchformulations can further contain a demulcent, a preservative, or acoloring agent.

The formulations of the disclosure can be provided as a salt and can beformed with many acids, including but not limited to hydrochloric,sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend tobe more soluble in aqueous or other protonic solvents that are thecorresponding free base forms. In other cases, the preparation may be alyophilized powder in 1 mM to 50 mM histidine, 0.1 wt % to 2 wt %sucrose, and/or 2 wt % to 7 wt % mannitol at a pH range of 4.5 to 5.5that is combined with buffer prior to use.

In another embodiment, the formulations of the present disclosure can beuseful for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of phytocannabinoid dissolved in a pharmaceutically acceptablecarrier. Among the acceptable vehicles and solvents that can be employedare water and Ringer's solution, an isotonic sodium chloride. Inaddition, sterile fixed oils can conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid and various terpenes can likewise be used inthe preparation of injectables. These solutions are sterile andgenerally free of undesirable matter. These formulations may besterilized by conventional, well known sterilization techniques. Theformulations can contain pharmaceutically acceptable auxiliarysubstances to approximate physiological conditions such as pH adjustingand buffering agents, toxicity adjusting agents, e.g., sodium acetate,sodium chloride, potassium chloride, calcium chloride, sodium lactate,and the like. The concentration of lipophilic natural compound in theseformulations can vary widely and can be selected primarily based onfluid volumes, viscosities, body weight, and the like, in accordancewith the particular mode of administration selected and the patient'sneeds. For IV administration, the formulation can be a sterileinjectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension can be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation can also be asterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.

In another embodiment, the formulations of the present disclosure can bedelivered by the use of liposomes which fuse with the cellular membraneor are endocytosed, i.e., by employing ligands attached to the liposome,or attached directly to the oligonucleotide, that bind to surfacemembrane protein receptors of the cell resulting in endocytosis. Byusing liposomes, particularly where the liposome surface carries ligandsspecific for target cells, or are otherwise preferentially directed to aspecific organ, one can focus the delivery of the lipophilic naturalcompound, metabolite, or ester thereof into the target cells in vivo.

The formulations can be administered as a unit dosage form. In such formthe preparation can be subdivided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation can bevaried or adjusted according to the particular application and thepotency of the active component. The composition can, if desired,contain other compatible therapeutic agents.

The amount of phytocannabinoid compound adequate to treat a disease(e.g. through modulation of VEGF, COX, cell proliferation), is definedas a “therapeutically effective” dose. The dosage schedule and amountseffective for this use, i.e., the “dosing regimen,” will depend upon avariety of factors, including the stage of the disease or condition, theseverity of the disease or condition, the general state of the patient'shealth, the patient's physical status, age, and the like. In calculatingthe dosage regimen for a patient, the mode of administration also istaken into consideration. An effective amount of the water solubleformulation of the present disclosure is an amount sufficient to achievethe intended purpose of a method of the present invention, such astreating a particular disease state in a subject (e.g. a human subject).One skilled in the art is capable of determining the appropriate dosage.

The dosage regimen also takes into consideration pharmacokineticsparameters well known in the art, i.e., the rate of absorption,bioavailability, metabolism, clearance, and the like (for example, thelatest Remington's, supra). The state of the art allows the clinician todetermine the dosage regimen for each individual patient and disease orcondition treated.

Single or multiple administrations of phytocannabinoid formulations canbe administered depending on the dosage and frequency tolerated by thepatient. The formulations should provide a sufficient quantity of activeagent to effectively treat the disease state. Lower dosages can be usedwhen the drug is administered to an anatomically secluded site incontrast to when administration is orally, into the blood stream, into abody cavity, or into a lumen of an organ. Substantially higher dosagescan be used in topical administration. Actual methods for preparingparenterally administrable lipophilic natural compound formulations areknown or apparent to those skilled in the art.

In other embodiments, at least 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg,or 1 g of the compound is present in the water soluble beverageformulation. In other embodiments, 0.1 mg to 2 g, 0.5 mg to 1 g, 1 mg to500 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 10 mg, or 1 mg to 5 mg oflipophilic natural compound is present in the water soluble beverageformulation.

After a pharmaceutical composition including the lipophilic naturalcompound of the present disclosure has been formulated in an acceptablecarrier, it can be placed in an appropriate container and labeled fortreatment of an indicated condition. For administration of the compound,such labeling can include, e.g., instructions concerning the amount,frequency, and method of administration.

The terms and expressions which have been employed herein are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding equivalents of thefeatures shown and described, or portions thereof, it being recognizedthat various modifications are possible within the scope of theinvention claimed. Moreover, any one or more features of any embodimentof the present disclosure may be combined with any one or more otherfeatures of any other embodiment of the present disclosure, withoutdeparting from the scope of the invention. For example, the features ofthe formulations are equally applicable to the methods of treatingdisease states described herein.

EXAMPLES

The following examples below are meant to illustrate certain embodimentsof the present disclosure, and are not intended to limit the scope ofthe invention, but instead to provide further detail in connection withwhat are presently deemed to be the most practical and preferredembodiments of the present disclosure.

Example 1

Water soluble compositions of the phytocannabinoid cannabidiol (CBD)were formulated by admixing cannabidiol oil with the non-ionicsurfactant macrogolglycerol hydroxystearate (polyoxyl 40 castor oil) atabout 1:10 weight ratio of oil to surfactant. The cannabidiol oilcontained 80 wt % cannabidiol (CBD). The polyoxyl castor oil (non-ionicsurfactant) was heated and stirred to a temperature of about 120° F.Then the cannabidiol oil was added slowly and mixed until a clearviscous emulsion phase formulation with dissolved CBD oil was formed(cannabidiol emulsion). Water was boiled at 212° F. The heated water wasthen slowly added to the cannabidiol emulsion until a crystal clearsolution was formed. During the emulsion phase, the mixture took on adark purple color. This color was also evident after the aqueous phasewhen the water became a part of the formulation. The only difference wasthat the purple was a lighter color. This color change was unexpected,and the net result is a visually desirable color that is much moreappealing to the consumer.

The weight percentage of each component in the water soluble compositionis presented in Table 1.

TABLE 1 Water Soluble Cannabidiol Composition Water Soluble CBD FormulaIngredients Wt % Cannabidiol Oil 3 (80 wt % CBD) Water 66.7Macrogolglycerol 30 hydroxystearate 40 Sodium Benzoate 0.06 PotassiumSorbate 0.04 Citric Acid 0.2 Total 100The water soluble formulation above was analyzed by HPLC and found tocontain 2.4 wt %, or 24 mg/ml cannabidiol. It is noted that in someembodiments, as shown in the table above, the formulation may alsoinclude pH modifiers, preservatives, etc., in minor amounts.

Example 2

1 ml of the formula prepared in accordance with Table 1 was furtherdissolved in 8 oz. of water to make an unsweetened, unflavored medicinalwater. The resulting beverage was crystal clear and remained soindefinitely.

Example 3

Water soluble compositions of grapefruit seed extract were formulatedcontaining macrogolglycerol hydroxystearate (polyoxyl 40 castor oil).Grapefruit seed extract is a natural preservative and is effectiveagainst both gram positive and gram negative bacteria. The polyoxyl 40castor oil was heated and stirred to a temperature of about 100° F. Thenthe grapefruit seed oil and a cannabidiol oil containing 80 wt %cannabidiol (CBD) were added slowly and mixed until a clear viscoussolution was formed containing dissolved grapefruit seed extract andcannabidiol oil. The clear emulsion was then slowly added to warm water(120° F.-180° F.) until a crystal clear solution was formed. The weightpercentage of each component in the formulation is presented in Table 2.

TABLE 2 Water Soluble Cannabidiol and Grapefruit Seed ExtractComposition Water Soluble CBD and Grapefruit Seed Extract FormulaIngredients Wt % Grapefruit seed Extract Oil 0.5% Cannabidiol Oil (80%CBD)  2% Water 67.1%  Macrogolglycerol  30% hydroxystearate 40 CitricAcid 0.2% Total 100% The water soluble formulation above contains 1.6 wt %, or 16 mg/mlcannabidiol. It is noted that in some embodiments, as shown in the tableabove, the formulation may also include pH modifiers, preservatives,etc., in minor amounts.

Example 4

The water soluble concentrate prepared in accordance with Table 2 can beadded to water, beverages, or other emulsions to make a crystal clear,water soluble preservative or drink that is effective against both grampositive and gram negative bacteria.

Example 5

Water soluble compositions of essential flavor oils were formulatedcontaining polyoxyl castor oil and an essential flavor oil. Mostessential flavor oils contain from about 20% to about 45% alcohol. Thepolyoxyl castor oil (non-ionic surfactant) was heated and stirred to atemperature of about 100° F., and a pure orange essential oil(containing no alcohol) was slowly mixed with the polyoxyl castor oiluntil a clear viscous solution was formed containing dissolved essentialorange oil. A cannabidiol hemp oil containing 80% cannabidiol was addedto this emulsion. The orange essential oil/cannabidiol emulsion was thenslowly added to warm water heated to between 120° F.-180° F. The warmwater had been previously boiled to sterilize. A crystal clear solutionwas formed.

TABLE 3 Water Soluble Cannabidiol and Orange Essential Oil CompositionWater Soluble CBD and Orange Essential Oil Composition Ingredients Wt %Orange Oil Flavor 1.25 Cannabidiol Oil 1 (80 wt % CBD) Water 72.45Polyoxyl castor oil 25 Sodium Benzoate 0.06 Potassium Sorbate 0.04Citric Acid 0.2 Total 100The water soluble formulation above contains 0.8 wt %, or 8 mg/mlcannabidiol. It is noted that in some embodiments, as shown in the tableabove, the formulation may also include pH modifiers, preservatives,etc., in minor amounts.

Example 6

The water soluble concentrate prepared in accordance with Table 3 can beadded to water, beverages, or other emulsions to make a crystal clear,water soluble drink with acceptable flavor without the need of analcohol containing essential oil extract.

Example 7

A pharmacokinetic, bioavailability (blood absorption) study wasconducted with the water soluble cannabidiol formulation from Example 1above. Male Sprague-Dawley rats were administered 50 mg doses by oralgavage. Blood plasma samples were collected at various intervals from0-24 hours, post dose, and the plasma concentration of cannabidiol wasdetermined by liquid chromatography/tandem mass spectrometry (LC-MS/MS).The animal data collected is shown in Table 4A. FIG. 1 displays theblood plasma level for each rat and the mean blood plasma level of thethree rats over a 24 hour period.

TABLE 4A Animal Data Oral (50 mg/rat, WS CBD) Rat #, Mean, or SD 1 2 3Mean SD 0 hour (pre-dose) 8.73 42.2 17.8 22.9 17.3 0.25 hour 103 56.865.3 75.0 24.6 0.5 hour 342 270 333 315 39.2 1.0 hour 681 696 673 68311.7 2.0 hours 1470 742 1050 1087 365 4.0 hours 1870 2110 1730 1903 1928.0 hours 1470 1280 1520 1423 127 24 hours 451 509 463 474 30.6 AnimalWeight (kg) 0.293 0.294 0.306 0.298 0.007 Dose (mg/kg) 171 170 163 1684.03 C_(max) (ng/mL) 1870 2110 1730 1903 192 t_(max) (hr) 4.0 4.0 4.04.0 0.0 t_(1/2) (hr) 9.64 10.3 10.1 10.0 0.347 MRT_(last) (hr) 8.65 9.158.93 8.91 0.250 AUC_(last) (hr · ng/mL) 26789 24958 26317 26021 951AUC_(∞) (hr · ng/mL) 33062 32526 33096 32895 320 Dose-normalized Value157 147 161 155 7.37 AUC_(last) (hr · kg · ng/mL/mg) Dose-normalizedVlaue 193 191 203 196 6.26 AUC∞ (hr · kg · ng/mL/mg) C_(max): maximumplasma concentration; t_(max): time of maximum plasma concentration;t_(1/2): half-life, data points used for half-life determination are inbold; MRT_(last): mean residence time, calculated to the last observabletime point; AUC_(last): area under the curve, calculated to the lastobservable time point; AUC_(∞): area under the curve, extrapolated toinfinity; ND: not determined; and Dose-normalized by dividing theparameter by the nominal dose in mg/kg.In Table 4A, pharmacokinetic parameters were determined with PhoenixWinNonlin (v6.3) software using a non-compartmental model. The maximumplasma concentration (c_(max)) and the time to reach maximum plasma drugconcentration (t_(max)) after oral dosing were observed from the data.The area under the time-concentration curve (AUC) was calculated usingthe linear trapezoidal rule with calculation to the last quantifiabledata point, and with extrapolation to infinity if applicable. Plasmahalf-life (t_(1/2)) was calculated from 0.693/slope of the terminalelimination phase. Mean residence time, MRT, was calculated by dividingthe area under the moment curve (AUMC) by the AUC. Any samples below thelimit of quantization (0.5 ng/mL) were treated as zero forpharmacokinetic data analysis.

Example 8

The concentration of drug in blood plasma against time was computedusing the linear trapezoidal rule to determine the area under the curve(AUC). The mean AUC value to infinity from above was compared topreviously determined cannabidiol oil absorption values for a typicallyavailable commercial formulation that was not dissolved in water andsurfactant as disclosed herein. The results indicate, as shown in Table4B, that the formulation from Example 1 exhibited approximately threetimes the absorption rate of the commercially available oil formulation.A graph of the absorption comparison is shown in FIG. 2.

TABLE 4B Absorption Comparison Data Total Absorption Level TreatmentAUC∞ (hr · kg · ng/mL/mg) Cannabidiol Oil 62 WS Cannabidiol Formulation196

While the above examples are illustrative of the principles and conceptsdiscussed herein, it will be apparent to those of ordinary skill in theart that numerous modifications in form, usage and details ofimplementation can be made without the exercise of inventive faculty,and without departing from those principles and concepts. Accordingly,it is not intended that the principles and concepts be limited, exceptas by the claims set forth below.

What is claimed is:
 1. A topical formulation, comprising a water-solublephytocannabinoid emulsion including a phytocannabinoid oil whichincludes a phytocannabinoid compound, and a non-ionic surfactant,wherein the weight ratio of phytocannabinoid compound content tonon-ionic surfactant is from 1:10,000 to 1:5.
 2. The topical formulationof claim 1, further comprising water.
 3. The topical formulation ofclaim 2, wherein the topical formulation is a non-alcoholic topicalformulation, a non-aprotic solvated topical formulation, or both.
 4. Thetopical formulation of claim 2, wherein the phytocannabinoid is presentat a concentration of at least 0.01 mg/ml.
 5. The topical formulation ofclaim 2, wherein the phytocannabinoid is present at a concentration ofat least 1 mg/ml.
 6. The topical formulation of claim 1, wherein thephytocannabinoid oil comprises hemp oil.
 7. The topical formulation ofclaim 1, wherein the topical formulation is devoid of water and thephytocannabinoid compound is present at a concentration of at least 0.1mg/ml.
 8. The topical formulation of claim 1, wherein the topicalformulation is devoid of water and the phytocannabinoid compound ispresent at a concentration of at least 1 mg/ml.
 9. The topicalformulation of claim 1, wherein the topical formulation comprises atleast about 10 mg of the phytocannabinoid compound.
 10. The topicalformulation of claim 1, wherein the non-ionic surfactant comprises amember selected from group consisting of a non-ionic water solublemono-, di-, or tri-glyceride; non-ionic water soluble mono- or di-fattyacid ester of polyethyelene glycol; non-ionic water soluble sorbitanfatty acid ester; polyglycolyzed glyceride; non-ionic water solubletriblock copolymers; or a derivative thereof.
 11. The topicalformulation of claim 1, wherein the non-ionic surfactant is a non-ionicwater soluble mono-, di-, or tri-glyceride.
 12. The topical formulationof claim 1, wherein the phytocannabinoid emulsion comprises cannabidiol.13. The topical formulation of claim 1, wherein the topical formulationis a transdermal formulation.
 14. The topical formulation of claim 13,wherein the phytocannabinoid compound is transdermally deliverable to asubject.
 15. The topical formulation of claim 2, wherein the topicalformulation is in the form of an applicator stick, a solution, a liquidsuspension or emulsion, a gel, a cream, an ointments, a paste, a jelly,a paint, a powder, or an aerosol.
 16. The topical formulation of claim2, wherein the water is present at greater than about 50 wt % and thetopical formulation, and the topical formulation is clear with novisible particles or micelles to the naked eye.
 17. The topicalformulation of claim 1, wherein the phytocannabinoid compound isselected from the group consisting of cannabidiol (CBD), cannabinol(CBN), cannabichromene (CBC), cannabichromenic acid (CBCA),cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG),cannabigerolic acid (CBGA), cannabigerivarin (CBGV), esters thereof,salts thereof, metabolites thereof, prodrugs thereof, and mixturesthereof.
 18. A method of preparing the topical formulation of claim 1,comprising combining the phytocannabinoid oil with the non-ionicsurfactant that is heated to at least 90° F.
 19. The method of claim 18,further comprising combining the phytocannabinoid oil that has beencombined with the non-ionic surfactant with water that is warmed to from90° F. to 200° F.
 20. A method of delivering a phytocannabinoid compoundto a subject, comprising topically administering the topical formulationof claim 1 to the subject, wherein the phytocannabinoid compound isdelivered to the subject with enhanced bioavailability compared todelivery of an undissolved or undispersed form of the phytocannabinoidoil.